Interaction between haematopoietic and mesenchymal stroma

Abstract

Parenchyma and stroma represent the functional and structural units in every organ of the body respectively. Stromal cells of mesenchymal origin (MSC) have traditionally been associated with a structural support activity within the tissue, but it is only recently that more complex functions have been unveiled. Subsets of MSC have been shown to play a fundamental role in self-renewal and differentiation of haematopoietic stem cells (HSC). Recent findings show that MSC and bone marrow (BM) macrophages represent fundamental components in the niche, modulating egress and mobilization of HSC during normal or emergency myelopoiesis. Therefore, I have decided to investigate whether and how MSC contribute to the formation and function of myeloid cells. In an in vitro co-culture model I have observed that MSC have the ability to induce the expansion and differentiation of different subsets of mature myeloid cells from haematopoietic BM cells. Based on the differential expression of CD11b and Gr-1, three cell subsets recapitulating myeloid differentiation could be identified. MSC induced differentiation targets common myeloid progenitors (CMP) or granulocyte/macrophage progenitors (GMP) but not the primitive HSC. CD11b+ sorted cells obtained at the end of the co-culture exhibited a functional profile characterised by high levels of both anti- and pro-inflammatory markers, such as nitric oxide synthase 2 (NOS2) and arginase-1 (ARG-1). In order to identify the mechanisms involved in this phenomenon I have chosen to investigate a number of molecules involved in the regulation of haematopoietic differentiation by the microenvironment. I have demonstrated that whilst NOS2 and agrin, an ECM protein, play a key role in the differentiation of CD11b+ Gr-1- F4/80+ cells, complement appears to be primarily involved in the generation of CD11b+ Gr-1int-low F4/80- cells. My studies have shown that MSC differentiating activity is not confined to the BM but can also be detected in MSC from other tissues like skin and kidney. Overall these results suggest a key role for stromal cells as regulators of myeloid differentiation. Further investigation is under way to assess the importance of such a function in vivo.